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The therapeutic usefulness of doxorubicin, an antineoplastic drug, is limited by its cardiotoxicity whose mechanism is as yet unknown. Several hypotheses have been postulated including also the release of vasoactive substances, so the aim of the present investigations was to study the relationship between the release of vasoactive substances and the development of doxorubicin-induced cardiotoxicity. The effects of the following drugs on doxorubicin-induced (cumulative dose of 20 mg/kg intraperitoneally) cardiotoxicity in rats have been evaluated: verapamil (1 and 10 mg/kg orally), that inhibits the slow channel influx of calcium and catecholamine release, acetylsalicylic acid (50 and 100 mg/kg orally), that inhibits the prostaglandin biosynthesis and release, and cromolyn sodium (cromolyn; 1 and 10 mg/kg orally), that inhibits the secretion of histamine. Our results showed that verapamil reduced and delayed doxorubicin-induced mortality, and limited doxorubicin-induced body weight decrease and ECG changes. Acetylsalicylic acid and cromolyn did not protect against doxorubicin-induced cardiotoxicity. These findings suggest that the release of vasoactive substances does not play a prevalent role in the development of doxorubicin-induced cardiotoxicity. The protective effect of verapamil is probably due to the inhibition of doxorubicin-induced intracellular calcium overload.

The endothelins are a recently discovered family of potent contractile peptides produced by endothelial cells. These peptides have been suggested to play an important role in the pathogenesis of hypertension, myocardial infarction, cardiogenic shock, and so on. The aim of our study was to compare the responses to endothelin-1 (ET-1) with those to L-noradrenaline (NA) in aortic rings from rats of different strains and ages. Thoracic aorta rings from spontaneously hypertensive (SHR), Wistar Kyoto (WKY), Brown Norway (BN) and spontaneously hyperlipemic (Yoshida, YOS) rats 2-4 (young), 6-8 (adult) and 20-25 (old) months old were used. There were no changes in the pD 2 values for ET-1 and NA between WKY and SHR rats at the ages studied. The ET-1 and NA Emax in adult SHR rats was significantly lower than in the age-matched WKY animals. Old age reduced the ET-1 and NA Emax in both SHR and WKY rats abolishing the difference observed at 6-8 months in the same groups. The reactivity to ET-1 and NA of BN and YOS rats was modified only in young rats. In YOS strain aging did not modify the ET-1 and NA responses as the pD 2 and Emax values remained unchanged. Our findings demonstrate that ET-1 is a more potent vasoconstrictor than NA and that this potency remains unchanged throughout the ages and the pathologies studied. In contrast, the pD 2 of NA decreases with old age in SHR and WKY rats. We conclude that rat strain but not hypertension or hyperlipemia can modify the response to ET-1 or NA in old age. We suppose that this functional change may involve alterations in the responsiveness of vascular smooth muscle.

We have investigated the effect of inhaled adenosine on bronchomotor tone in 16 healthy and 24 allergic and non-allergic bronchopathic subjects. We determined the inhaled adenosine dose-response curves after no treatment and after treatment with aminophylline (240 mg in 10 min), reproterol (90 mcg in 2 min) and salbutamol (100 mcg in 2 min) administered intravenously 15 min before adenosine and reproterol (500 mcg) and salbutamol (200 mcg) administered by inhalation from a metered aerosol 30 min before adenosine on separate days. Without prior treatment, inhaled adenosine caused bronchoconstriction in both groups of subjects (normal, and atopic and non-atopic asthmatic ones), but the peripheral airways revealed only a moderate change in normal subjects. Aminophylline caused a greater inhibition of adenosine bronchoconstriction than did reproterol. These results suggest that inhaled adenosine bronchoconstriction involved purinergic transmission and that it is mediated via a P1/Ri (A-1/R1) receptor. Aminophylline is a potent antagonist at purinoceptor level. Reproterol inhibits bronchoconstriction by a mechanism independent of its effect on beta-adrenergic receptors. Because salbutamol, i.e. a beta 2-agonist bronchodilator, did not inhibit adenosine-induced bronchoconstriction (or very nearly so), our results support the view that reproterol antagonizes P1/Ri (A1/R1) tracheobronchial receptors.

The present experiments evaluated in rats the effects of prenatal and postnatal exposure to a non-steroidal antiinflammatory agent, flunoxaprofen (5-10 and 20 mg/kg/day by the oral route), on cardiovascular function in the pups. In both conscious and anaesthetized rats pre- and postnatal flunoxaprofen exposure at the 30th and 60th day of age, significantly (P less than .05) induced a decrease of pressor response to carotid-sinus baroreceptor stimulation and to L-noradrenaline (0.1-1 and 5 micrograms/kg iv), and an increase of the hypotensive responses to L-isoprenaline (0.01-0.1 and 1 microgram/kg iv) and acetylcholine (0.01-0.1 and 1 microgram/kg iv). These effects were not observed in rats on the 90th day of age. Moreover, pre- and postnatal flunoxaprofen exposure did not modify systolic arterial blood pressure of plasma levels of catecholamines and acetylcholinesterases. Our results also show that in normotensive rats flunoxaprofen exposure during pregnancy did not affect the body weight, systolic or diastolic blood pressure or heart rate of pregnant rats. It did not affect the length of gestation, number of pups per litter or pup body weight. No macroscopic teratogenic effects were observed.

Spermidine (SPD) and spermine (SPM) produced in anaesthetized dogs significant cardiovascular changes at higher doses than other transmitters, i.e. l-noradrenaline, l-adrenaline, histamine, acetylcholine, which produce cardiovascular effects at doses of 0.01-0.05 micrograms/kg given intravenously. SPD was shown to be more active than SPM. The hypotensive response observed after i.v. injection is due to histamine release. The hypotensive and bradycardic effects observed after microinjection of SPD into III cerebral ventricle or into the vertebral artery and of SPM into the vertebral artery are due to an increase in parasympathetic output. Spermidine increased and spermine decreased the baroreceptor reactivity. SPD and SPM did not change the vascular beta- and alpha-adrenergic, cholinergic and histaminergic receptor reactivity.

A group of ethyl 2-methylimidazo[1,2-a]pyrimidine-3-carboxylates were prepared by reaction of ethyl 2-chloroacetoacetate with some 2-aminopyrimidines. These ethyl esters were then converted into the corresponding carboxylic acids via alkaline hydrolysis. The acids so obtained were evaluated for antiinflammatory, analgesic, antipyretic and ulcerogenic activities.

A series of N,N-dialkyl 5-trans-carbamoyloxy-1,2,3,3-tetramethyl-2-azabicyclo [2,2,2]octanes was prepared by reaction of 1,2,3,3-tetramethyl-2-azabicyclo [2,2,2]octan-5-trans-ol with phosgene, followed by aminolysis of the resulting chlorocarbonate with aliphatic secondary amines. 5-Chloro-1,2,3,3-tetramethyl-2-azabicyclo [2,2,2] octane (cis/trans mixture) was isolated as by-product of the reaction. A number of urethanes showed antiarrhythmic activity in guinea pigs and mice, as well as surface anesthesia in rabbits and infiltration anesthesia in mice, superior or similar to lidocaine. The circulatory, cardiac and respiratory effects in dogs and hens are also described.

A group of ethyl 2-methylimidazo[1,2-a]pyrimidine-3-carboxylates were prepared by reaction of ethyl 2-chloroacetoacetate with some 2-aminopyrimidines. These ethyl esters were then converted into the corresponding carboxylic acids via alkaline hydrolysis. The acids so obtained were evaluated for antiinflammatory, analgesic, antipyretic and ulcerogenic activities.

Exposure to drugs during pregnancy can alter functional development of the vascular system. The present investigation was carried out in order to evaluate the effects of prenatal and postnatal exposure to Ca2+-antagonist (diltiazem, verapamil, and nimodipine) drugs on the development of rat vasomotor reactivity. Studies were carried out on pregnant female albino rats exposed from the first day of pregnancy until weaning to diltiazem and verapamil (6 and 24 mg/kg in their drinking water ad libitum) and nimodipine (3 and 12 mg/kg in their food ad libitum). After weaning, pups were exposed until the 60th day of age to the same treatment as their mothers were. Afterwards, pups from the 60th to 90th day of age were fed with a normal diet. In 30-, 60-, and 90-day-old conscious and anaesthetized pups, we evaluated the following: 1) systolic arterial blood pressure; 2) vasomotor responses elicited by various agents: L-noradrenaline (0.1, 1, and 5 micrograms/kg IV), L-isoprenaline (0.01, 0.1, and 1 micrograms/kg IV), and acetylcholine (0.01, 0.1, and 1 micrograms/kg IV) and by sinus-carotid baroreceptor stimulation; and 3) catecholamine, acetylcholinesterase, and adenosinase plasma levels. Prenatal and postnatal exposure to Ca2+-antagonist drugs significantly (P less than .05) decreased the pressor response to sinus-carotid baroreceptor stimulation and to L-noradrenaline and increased the hypotensive responses to L-isoprenaline and acetylcholine. Moreover, this type of treatment, although it induced a significant (P less than .05) decrease of catecholamine plasma levels, did not modify the acetylcholinesterase and adenosinase plasma levels in 30- and 60-day-old rats. On the 90th day of age, the evaluated parameters were not different from those of control rats. Our results showed that exposure to Ca2+ antagonists during pregnancy and the postnatal period may alter the functional development of rat vasomotor reactivity.

The aim of this retrospective observational study was to investigate: a) expenditure for antibiotics with respect to the total pharmacy drug budget and to costs of other medical devices; b) the most frequently used antimicrobial classes and molecules; c) the clinical units that most frequently use antimicrobial therapy; d) the preferred route of administration; e) consumption patterns of antibiotics over two periods (January-September 1999 and January-September 2000). The consumption of a single antimicrobial agent was expressed as daily defined doses (DDD) per 100 bed days. In 1999 drugs accounted for 56% of the total costs but decreased to 46% in 2000. Antibiotics accounted for 15% of the pharmacy's overall acquisition costs in 1999 and dropped to 13% in 2000. In both 1999 and 2000, penicillins were used most, followed by cephalosporins and aminoglycosides. In 1999, the most frequently used antibiotic was amoxicillin (4.02 DDD per 100 bed days) followed by ceftazidime, ampicillin, ceftriaxone, and co-amoxiclav. In 2000 ceftriaxone was the most commonly used antibiotic (4.35 DDD per 100 bed days) followed by co-amoxiclav, amoxicillin, ceftazidime. The general surgery, medical therapy and infectious diseases units accounted for the majority of penicillin consumption, while cephalosporins were most widely used in general surgery, orthopedics and neurosurgery units. Parenteral administration was the most widely used route in both years.

The synthesis of a series of 1-aryl-1,6-dihydro-4H-thieno[3,4-c]pyrazol-4-ones by cyclization of 3-[(2-arylhydrazino)methylene]thiophene-2,4(3H,5H)-diones, prepared by reacting 3-dimethylaminomethylenethiophene-2,4(3H,5H)-dione with arylhydrazines, is described. The 4-fluorophenyl derivative showed remarkable analgesic, antiinflammatory and antipyretic activities in mice or rats, as well as a platelet antiaggregating activity in vitro comparable to that of acetylsalicylic acid.

The anti-inflammatory, analgesic and antipyretic activities of S-(+)-2(4-fluorophenyl)-alpha-methyl-5 benzoxazole acetic acid (flunoxaprofen: Flu), a new non-steroidal anti-inflammatory drug, were compared with those of indomethacin and other non-steroidal anti-inflammatory drugs (NSAIDs) in experimental animals. Flu showed strong inhibitory activity on acute and subacute inflammation tests in rats, such as carrageenin hind paw oedema (oral: 6-25 mg/kg; rectal: 50-100 mg/kg); pellet-induced granuloma formation (5-20 mg/kg/day) and adjuvant-induced arthritis (10 mg/kg/day). Its potency was comparable with that of indomethacin (I) and higher than that of acetyl salicylic acid (ASA), ibuprofen (IBU) or phenylbutazone (P). The analgesic activity of Flu, evaluated by the hot plate method and tail pinching in mice, was slightly lower than that of I but higher than that of ASA and IBU. In pyretic rabbits Flu showed an antipyretic activity higher than that of ASA and IBU. The ability of Flu to affect platelet aggregation, mucopolysaccharide synthesis by fibroblasts and the proteolytic action of trypsin was also investigated.

This was a 9-month observational prospective study conducted in two steps to evaluate surgical prophylaxis procedures used by surgeons in several departments of the Second University of Naples (SUN). In step 1 (4 months), we collected and analyzed data on surgical interventions and antibiotic prophylaxis. Surgeons were informed of the analysis outcome and were given an antibiotic prophylaxis protocol based on international guidelines. In step 2 (5 months), we collected data on surgical interventions and antibiotic prophylaxis, and compared them with step 1 data. The analysis of 354 forms (step 1) showed that third-generation cephalosporins were the preferred prophylactic antibiotics. The analysis of 369 forms (step 2) showed that ceftriaxone and ampicillin were the most frequently used antibiotics. Surgeons did not comply with guidelines for antibiotic prophylaxis as regards type of antibiotic and treatment duration but implementation of antibiotic prophylaxis protocols resulted in more appropriate and better timing of antibiotic prophylaxis.

The effects of flunoxaprofen (FL) were investigated using anesthetized normotensive and spontaneously hypertensive (SHR) young and old rats. The animals were divided into two groups. One group received a non-steroidal anti-inflammatory agent at doses significantly inhibiting prostaglandin (PG)-cyclooxygenase; the other received no non-steroidal anti-inflammatory drugs. Oral pretreatment of anesthetized rats with flunoxaprofen (6.6, 11.5, and 19.9 mg/kg/day in the feed for 560 days) significantly increased the following responses: occlusion of the common carotid arteries, and reactivity to L-noradrenaline (NA) (i.v.), and angiotensin II (Ang) (i.v.). Pressor responses also increased in normotensive and in SHR rats treated with FL (20 mg/kg/day for seven days). The effects were more intense in the SHR rats. Moreover, oral pretreatment of normotensive rats with FL (20 mg/kg/day for seven days) partially yet significantly reduced the antihypertensive activity of etozolin (ET), a diuretic and antihypertensive drug. Our data confirm the important role of prostaglandins in the regulation of the cardiovascular system, and an increase in arachidonic acid metabolite biosynthesis with vasodilatory effects being part of the mechanism of action of some antihypertensive drugs.

Abstract We investigated the possible relationship between endothelin-1 injection into the dorsolateral periaqueductal gray area and the glutamatergic system in the control of cardiovascular function. Endothelin-1 was injected into the dorsolateral periaqueductal gray area of freely moving rats at doses ranging from 0.1 to 10 pmol. Endothelin-1 increased arterial blood pressure (from 7.0±1.6 to 55.0±4.1 mm Hg, mean±SEM) in a dose-dependent manner and induced characteristic behavioral changes such as longitudinal rolling of the body (barrel-rolling). dl -2-Amino-5-phosphonovaleric acid and (5 R ,10 S )-(+)-5-methyl-10,11-dihydro-5 H -dibenzo[ d -α]cyclohepten-5,10-imine hydrogen maleate, both selective N -methyl- d -aspartate excitatory amino acid receptor antagonists, but not 6-cyano-7-nitroquinoxaline-2,3-dione, a non– N -methyl- d -aspartate excitatory amino acid receptor antagonist, significantly decreased endothelin-1–induced cardiovascular and behavioral changes ( P N -methyl- d -aspartate receptors, a significant influence on endothelin-1–induced cardiovascular and behavioral effects after its injection into the periaqueductal area.

Fructose-1,6-diphosphate (FDP) has been reported to exert beneficial effects on several cardiac functions. We studied the effects of FDP on the biochemical and dynamic functions of the heart in anesthetized dogs. Significant effects of FDP were noted mostly as related to pyruvate and lactate metabolism. The results seem to indicate that FDP may improve heart metabolism, and coronary function in restricted animals.

The effects of one of the main components of fish oil, docosahexaenoic acid (DHA), on prostaglandin (PG) and Ca2+ signaling pathways were examined in intact mucosa and freshly isolated crypt cells of rabbit descending colon. Preincubation of serosal mucosa for 20 min with 1 microM DHA fully suppressed the short-circuit and transepithelial conductance increase induced by serosal addition of 10 microM arachidonic acid (AA). DHA at 1 microM also prevented the Cl- secretion promoted by 10 microM AA, as estimated by unidirectional 36Cl flux measurements (net flux = 0.68 +/- 0.30 versus -1.91 +/- 0.20 microEq/hr/cm2, four experiments, p0.001), whereas it did not affect the electrophysiological and ion flux responses to PGE2. Addition of 1 microM DHA to the serosal side of the mucosa also inhibited the PG cascade activation elicited by AA (PG synthesis and second messenger cAMP increase). In vitro assays of colonic cyclooxygenase activity showed that 1 microM DHA inhibited (with a 20-min lag) cyclooxygenase activity to the same extent as 5 microM indomethacin (approximately 82% and 80%, respectively). DHA also affected the Ca2+ signaling pathway; in isolated crypt cells, the cytosolic free Ca2+ concentration ([Ca2+]i) dropped by 49 +/- 7.6% (mean +/- standard error, six experiments) after incubation with 1 microM DHA. The sustained phase of the [Ca2+]i response to 500 nM concentrations of the intracellular Ca(2+)-ATPase inhibitor thapsigargin was also inhibited within 150 sec upon 1 microM DHA addition (141 +/- 5.8 versus 243 +/- 8.2 nM [Ca2+]i mean +/- standard error, eight experiments, p0.01). The [Ca2+]i-lowering effect of DHA, which was not achieved by incubation with other free fatty acids, was not prevented by removal of Na+ from the incubation medium (-46 +/- 4.3% versus -47 +/- 3.8%, mean +/- standard error, four experiments), nor it was mediated by cAMP-, protein kinase C-, or calmodulin-dependent mechanisms. The incubation of highly purified basolateral membranes of crypt cells with 1 microM DHA for 1 min produced a 5-fold increase (IC50 = 0.25 microM) in the plasma membrane Ca(2+)-ATPase activity (34.3 +/- 2.73 versus 6.02 +/- 0.50 nmol/mg of protein/min, mean +/- standard error, four experiments, p0.0001), thus indicating that the DHA effects on the Ca2+ pathway were mediated mainly by an increase in plasma membrane Ca2+ pump activity. These findings suggest that DHA is a powerful modulator of the cellular response to activation of PG and Ca2+ signaling pathways.

The aim of the present study was to evaluate the effects of hyperbaric oxygen (HBO) therapy on multiple organ failure induced by zymosan. Administration of zymosan (500 mg/kg) in the rat induced neutrophil infiltration in the lung, liver, and intestine as evaluated by increase in myeloperoxidase (MPO) activity. Therefore, lipid peroxidation was significantly increased in zymosan-treated rats. This inflammatory process coincided with the damage of lung, liver, and small intestine. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine in the lung, liver, and small intestine of zymosan-shocked rats. HBO (2 absolute Atmosphere) exposure attenuates the increase in the tissue levels of MPO and malondialdehyde (MDA) caused by zymosan in the lung, liver, and intestine. In addition, HBO (2 absolute Atmosphere) was effective in preventing the development of lung, liver, and intestine injury. Taken together, the present results demonstrate that HBO may also be an efficacious treatment in multiple organ failure induced by zymosan.

To investigate the relationship among the number of platelets and plasma levels of S-nitrosothiols (S-NO), nitrite, total non-protein SH (NPSH), glutathione (GSH), cysteine (CYS), malondialdehyde (MDA), 4-hydroxininenal (4HNE), tumor necrosis factor-alpha (TNFalpha) and interleukin (IL)-6 in patients with chronic hepatitis C (CH).In vitro the aggregation of platelets derived from controls and CH patients was evaluated before and after the addition of adenosine diphosphate (ADP) and collagen, both in basal conditions and after incubation with nitrosoglutathione (GSNO).In vivo, S-NO plasma levels increased significantly in CH patients and they were significantly directly correlated with platelet numbers. Patients with platelet counts150000/microL, had a smaller increase in S-NO, lower levels of GSH, CYS, NPSH, TNFalpha, and IL-6, and higher levels of nitrite, MDA, and 4-HNE relative to those of patients with platelet counts150000/microL. In vitro, the ADP and collagen aggregation time was increased in platelets from patients and not from controls; in addition, platelets from CH patients but not from controls also showed a latency time after exposure to collagen.The incubation of platelets with GSNO improved the percentage aggregation and abolished the latency time.